PROJECT SUMMARY Although signaling from phosphoinositide 3-kinase (PI3K) to the mechanistic target of rapamycin (mTOR) features prominently in glioblastoma, inhibitors that target PI3K and mTOR have failed in patients with glioblastoma. In published and preliminary data presented in this application, we identified the mTOR target p- 4EBP1 as a robust biomarker for therapeutic response. We further show that the failure of PI3K and mTOR inhibitors tested in glioblastoma patients is not because these targets and pathways are unimportant, but because agents used clinically fail to target 4EBP1. We have now identified and tested a new class of 4EBP1 inhibitors (developed by UCSF collaborator Kevan Shokat) that potently block 4EBP1 in glioblastoma in-vivo, leading to robust improvement in survival in preclinical orthotopic models of GBM. Our proposal develops this class of drugs for clinical use, evaluating a clinical 4EBP1 inhibitor, and providing a precision medicine path forward for a clinical trial in patients with glioblastoma. This clinical agent, Rev1, is available collaboratively with Revolution Medicines, a company co-founded by Dr. Shokat. While glioblastoma was not initially part of Revolution Medicine's clinical program, this SPORE incentivizes testing of Rev1 in glioma. We will test Rev1 in an early phase clinical trial by year 4 for this SPORE. The SPORE mechanism therefore provides a unique opportunity to test the hypothesis that clinical agents derivatized from RapaLink-1 represent potent clinical inhibitors of 4EBP1, and will be highly active in relevant subpopulations of GBM. Our specific aims are: Aim 1. To define the optimal glioma sub-population for clinical trials using inhibitors of 4EBP1 Aim 2. To optimize the efficacy of 4EBP1 inhibitors for clinical development. Aim 3. To design and conduct a phase IB clinical trial with Rev1 in pathway-activated recurrent glioblastoma.